Liver Peroxisomes and Bile Acid Formation

Abstract

Bile acid conjugates are main excretory products of cholesterol catabolism. 3a,7a,12a-Trihydroxy-53-cholestanoic acid (THCA) and 3a,7a-dihydroxy-53-cholestanoic acid (DHCA) are immediate precursors to the primary bile acids, cholic acid and chenodeoxycholic acid, respectively. Subcellular fractionation studies have shown that the peroxisomal fractions from both rat and human liver catalyze most efficiently the conversion of THCA into cholic acid and DHCA into chenodeoxycholic acid. The mechanism for this C27-steroid side chain cleavage reaction is similar to that of the peroxisomal 3-oxidation of long chain fatty acids. Rat liver peroxisomes also have the ability to conjugate the end products of the reaction, the CoA esters of the bile acids, with glycine or taurine.The importance of liver peroxisomes in vivo has been evaluated by studies of bile acid formation in patients with Zellweger syndrome, a fatal inherited disease with absent peroxisomes in liver and kidney. Bile and plasma of these patients contain high amounts of THCA and other bile acid intermediates with an uncleaved steroid side chain. By in vivo and in vitro studies we have shown that this accumulation is due to a defective peroxisomal oxidation of the side chain of THCA and DHCA. The accumulated THCA is converted to more polar secondary metabolites, presumably by microsomal enzymes. The pool size and the synthetic rate of cholic acid were reduced to about 1/10 of normal. We conclude that liver peroxisomes are essential for normal formation of bile acids in man.KeywordsBile AcidCholic AcidChenodeoxycholic AcidZellweger SyndromePrimary Bile AcidThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.